Testing a Novel DMD Therapeutic in MDX Mice

描述(由申请人提供)：药理学上上调促性腺激素已被提出为治疗DMD的一种治疗策略。遗传学研究表明，增加utroin的表达可以弥补dystrophin的丢失，纠正mdx小鼠的营养不良病理。然而，人类尚不能通过遗传方法上调中性粒细胞的水平。Biglycan是一种细胞外蛋白，是dystrophin复合体的一个组成部分，并与a-dystroglan(Bowe等人，2000年)、a-和？-肌聚糖(Rafii等人，2006年)结合。重组的Biglycan蛋白可以被传递到体内的肌肉中，在那里它可以挽救Biglycan缺失小鼠细胞内DAPC组分的肌膜表达(Mercado等人，2006年)。在拟议的研究中，我们将使用MDX小鼠来测试Biglycan作为治疗DMD的潜在疗效。在初步实验中，我们已经证明，系统地将纯化的重组Biglycan蛋白输送到mdx小鼠体内，上调了utroin的表达，并减少了肌纤维死亡和单核细胞浸润。此外，在治疗实践水平上单次注射的有效时间长达三周。在拟议的研究中，我们将生产重组双聚糖，并使用组织病理学标志物来确定其最佳给药剂量、频率和给药途径(S)。然后将进行功能研究，以确定Biglycan治疗是否改善MDX小鼠的骨骼肌功能。来自这些研究的积极数据将形成快速将这种治疗方法转化为临床试验的基础。Duchenne肌营养不良症(DMD)是最常见的遗传性肌营养不良症。目前没有有效的治疗方法，受影响的男孩12岁时被轮椅束缚，30岁时死亡。在拟议的研究中，我们将进行关键的临床前研究，以测试一种治疗DMD的新方法。

DESCRIPTION (provided by applicant): The pharmacological upregulation of utrophin has been proposed as a therapeutic strategy for treating DMD. Genetic studies show that increasing utrophin expression can compensate for the loss of dystrophin and correct dystrophic pathology in the mdx mouse. However, genetic approaches for utrophin upregulation are not yet feasible in humans. Biglycan is an extracellular protein that is a component of the Dystrophin complex and binds to a-dystroglycan (Bowe et al., 2000), a - and ?- sarcoglycan (Rafii et al., 2006). Recombinant biglycan protein can be delivered to muscle in vivo where it rescues the sarcolemmal expression of intracellular DAPC components in biglycan null mice (Mercado et al., 2006). In the proposed studies we will use mdx mice to test the potential efficacy of biglycan as a therapeutic for DMD. In preliminary experiments we have shown that purified recombinant biglycan protein delivered systemically to mdx mice upregulates utrophin expression and decreases myofiber death and mononuclear infiltration. Moreover, single doses at therapeutically-practical levels are effective for up to three weeks. In the proposed studies we will produce recombinant biglycan and use histopathological markers to determine the optimal dose, frequency and route(s) of administration for its use. Functional studies will then be carried out to determine whether biglycan treatment improves the function of skeletal muscle in mdx mice. Positive data from these studies would form the basis for a rapid translation of this therapeutic approach to clinical trials. Duchenne Muscular Dystrophy (DMD) is the most common form of inherited muscular dystrophy. Currently there are no effective treatments and affected boys are wheelchair bound by age twelve and die by their third decade. In the proposed studies we will perform critical preclinical studies to test a novel therapy for DMD.